What is the incidence/ risk of QTc prolongation when using high-dose ondansetron (e.g. 8 mg q6h) for the management of nausea and vomiting?

Comment by InpharmD Researcher

Evidence suggests that ondansetron prolongs the QT interval in a dose-dependent manner, with an increase of approximately 6 milliseconds observed after an 8 mg dose. However, due to available data primarily assessing single-dose administration, the specific incidence of QT prolongation associated with multiple doses of ondansetron (e.g., 8 mg Q6H) remains unclear.

Background

In 2011, the Food and Drug Administration (FDA) issued a warning regarding abnormal heart rhythms (including Torsades de Pointes) associated with ondansetron use. This was primarily seen with the 32 mg dose, which was discontinued in 2012. Specifically, at the highest tested single intravenous dose of 32 mg, the maximum mean difference in QTcF from placebo after baseline-correction was 20 msec. At the lower tested single intravenous dose of 8 mg, the maximum mean difference in QTcF from placebo after baseline-correction was 6 msec. [1]

Additionally, there are articles published in the medical literature that describe QT interval prolongation with ondansetron. Additional recommendations for ECG monitoring in patients with electrolyte abnormalities (e.g., hypokalemia or hypomagnesemia), congestive heart failure, bradyarrhythmias, or in patients taking other medications that can lead to QT prolongation, were also added to the ondansetron drug labels. [1]

According to the FDA Adverse Event Reporting System (FAERS) public dashboard, a total of 852 cases of ondansetron-associated electrocardiogram QTc prolongation, including 74 attributed deaths, have been reported from 2011 to 2024. Of note, this data is not specific to a particular dosage, and FAERS data may not accurately reflect the true occurrence of adverse effects in U.S. populations due to unverified, incomplete, or duplicate reports. [2]

A 2023 meta-analysis evaluated the occurrence of QT prolongation in pediatric, adult, and elderly patients receiving oral or intravenous ondansetron at doses below 32 mg. A total of 10 studies involving 687 participants were included. Findings revealed a statistically significant prevalence of QT prolongation across all age groups (0.14; 95% confidence interval [CI] 0.08 to 0.20; p <0.00001; I2= 96.3%); however, high heterogeneity was noted, and limitations such as small sample sizes, non-standardized dosing and routes of administration, and limited follow-up reduced the reliability of the results. Additionally, while a statistically significant increase in QT intervals was observed, its clinical significance remains unclear. Further research is needed to determine the impact of QT prolongation on clinical outcomes across varying dosages. [3]

References:

[1] Food and Drug Administration (FDA). FDA Drug Safety Communication: New information regarding QT prolongation with ondansetron (Zofran). Updated December 11, 2017. Accessed November 19, 2024.
[2] U.S. Food & Drug Administration. FDA Adverse Event Reporting System (FAERS) Public Dashboard. Updated September 30, 2024. Accessed November 19, 2024. https://fis.fda.gov/sense/app/95239e26-e0be-42d9-a960-9a5f7f1c25ee/sheet/45beeb74-30ab-46be-8267-5756582633b4/state/analysis
[3] Singh K, Jain A, Panchal I, et al. Ondansetron-induced QT prolongation among various age groups: a systematic review and meta-analysis. Egypt Heart J. 2023;75(1):56. Published 2023 Jul 3. doi:10.1186/s43044-023-00385-y
Literature Review

A search of the published medical literature revealed 2 studies investigating the researchable question:

What is the incidence/ risk of QTc prolongation when using high-dose ondansetron (e.g. 8 mg q6h) for the management of nausea and vomiting?

Level of evidence

C - Multiple studies with limitations or conflicting results  Read more→


Please see Tables 1-2 for your response.

 

A Randomized, Double-blind, Four-period Crossover Study to Investigate the Effect of Intravenous Ondansetron, a 5-HT3 Antagonist, on Cardiac Conduction as Compared to Placebo and Moxifloxacin in Healthy Adult Subjects

Design

Randomized, blinded, single-dose, period-balanced, crossover, placebo-controlled, pharmacodynamic study

N=58

Objective

To define the electrocardiographic effects of ondansetron in healthy volunteers

Study Groups

Ondansetron 8 mg (n=58)

Ondansetron 32 mg (n=56)

Placebo (n=57)

Moxifloxacin (n=57)

Inclusion Criteria

 Healthy adult men and women; aged 18-45 years; no cardiac conduction abnormalities

Exclusion Criteria

 None reported

Methods

Each participant was randomized to receive a single dose of ondansetron 8 mg IV over 15 mins, ondansetron 32 mg IV over 15 minutes, placebo (normal saline) IV over 15 minutes, or moxifloxacin 400 mg PO. Patients were monitored for 24 hours after dosing. After a minimum of 7 days washout, subjects returned and were randomized to another treatment; this happened until all treatment groups had been given.

Duration

 Up to 24 hours post medication administration

Outcome Measures

 ddQTcF change from placebo

Baseline Characteristics

  

All patients (n=58)

    

Age, years

 28.7 ± 7.07    

Female

36 (62%)    

Hispanic or Latino

 32 (55%)    

BMI, kg/m2

 25.9 ± 3.05    

Results

   Ondansetron 8 mg (n=58) Ondansetron 32 mg (n=56) Moxifloxacin (n=57)

ddQTcF change from placebo

15 mins

20 mins

30 mins

1 hour

2 hours

3 hours

4 hours

6 hours

12 hours

24 hours

 

5.84

3.54

3.53

2.26

1.07

0.34

0.43

-0.42

0.60

-0.72

 

17.94

19.57

15.52

9.89

7.14

4.65

4.60

1.08

2.86

0.51

 

1.17

-1.50

3.29

8.77

9.12

10.33

10.94

8.69

7.81

4.63

QTcF between 450-480 ms

15 mins

20 mins

30 mins

1 hour

2 hours

3 hours

4 hours

6 hours

12 hours

24 hours

Any: 2 (3%)

1 (2%)

1 (2%)

-

-

-

-

1 (2%)

-

-

-

Any: 9 (16%)

7 (13%)

7 (13%)

1 (2%)

3 (5%)

1 (2%)

-

-

-

-

-

Any: 3 (5%)

-

-

1 (2%)

2 (4%)

2 (4%)

1 (2%)

1 (2%)

-

-

-

No subject had a QTcF interval that was above 480 ms. The only time a change in QTcF between 30-60 ms occurred was within the first 20 minutes of exposure to ondansetron 32 mg. No subject experienced a change >60 ms. No significant changes were seen in the measured electrocardiographic PR or QRS intervals.

Adverse Events

Two patients reported ventricular tachycardia, one in the ondansetron 8 mg group and one with placebo.

Study Author Conclusions

 The ondansetron 8 mg IV dose given over 15 minutes resulted in ddQTc prolongation of 5.8 (7.8 upper bound) ms. The ondansetron 32 mg IV dose given over 15 minutes resulted in ddQTc prolongation of 19.6 (21.5 upper bound) ms. The upper bound for the ondansetron 32 mg IV dose remained >10 ms during the two hours following the 15-minute infusion.

InpharmD Researcher Critique

 This was an unpublished study conducted by GlaxoSmithKline. It was conducted in healthy, young individuals. Although the planned enrollment was 60 patients, one was lost to follow-up and one discontinued due to an adverse event (specifics not reported).



References:

GlaxoSmithKline. A Randomized, Double-blind, Four-period Crossover Study to Investigate the Effect of Intravenous Ondansetron, a 5-HT3 Antagonist, on Cardiac Conduction as Compared to Placebo and Moxifloxacin in Healthy Adult Subjects. Available from: https://www.gsk-studyregister.com/en/trial-details/?id=115458. June 20, 2012. Accessed January 22, 2021.

 

Evaluation of Ondansetron-induced QT Interval Prolongation in the Prophylaxis of Postoperative Emesis

Design

Prospective randomized, placebo-controlled, double-blind study

N=136

Objective

To evaluate the effect of 1 mg, 4 mg, and 8 mg bolus doses of intravenous Ondansetron, relative to placebo, in prevention of postoperative nausea and vomiting (PONV) and to find out the changes of QT interval corrected for heart rate (QTc)

Study Groups

Ondansetron 1 mg (n= 34)

Ondansetron 4 mg (n=34)

Ondansetron 8 mg (n=34)

Placebo (n=34)

Inclusion Criteria

ASA physical Status I and II; on no prescription of over-the-counter medication; with normal baseline electrocardiograms posted for breast surgery; vaginal hysterectomy; skin grafting surgery and reconstructive limb surgery were included in this study.

Exclusion Criteria

history of gastrointestinal disease; hormonal therapy; evidence of uncontrolled clinically important neurological, renal; hepatic; cardiovascular, metabolic or endocrine dysfunction or clinically important abnormalities in laboratory screening tests, vomiting during the 24-h period before surgery, VAS> 4 at extubation; if the participants were not extubated after 30 min following study medication, were not responding to verbal commands after extubation; reaction to the study drug, had a nasogastric tube in situ postoperatively, weighed <45 kg Or >90 kg; or were pregnant or lactating women.

Methods

One hour before skin closure, the participants were randomly allocated into four groups with 34 participants in each group through a computer-generated random number.

Intravenous metoclopramide 10 mg was used as rescue antiemetic.

Duration

360 minutes

Outcome Measures

Primary: Time to first rescue antiemetic medication in each group.

Secondary: Changes in QTc interval at different time intervals in each group.

Baseline Characteristics

  

Placebo (n=34)

Ondansetron 1 mg (n= 34)

 Ondansetron 4 mg (n= 34) Ondansetron 8 mg (n= 34) 

Age, years

 40 ± 4.3 42 ± 0.2 42 ± 1.4 40 ±5.3

Male

 40% 44% 40% 52%

BMI, kg/m2

 22.4 ±1.2 23.4 ± 0.12 22.6 ± 2.12 22.6 ± 2.12

Duration of anesthesia, min

 90 ± 41.3 100 ±22.6 90 ± 34.3 90 ±44.3

Results

ΔQTc over time, ms

Placebo (n=34)

Ondansetron 1 mg (n= 34)

Ondansetron 4 mg (n= 34)

 Ondansetron 8 mg (n= 34) 

1 min

 0.34 ± 0.02 0.36 ± 0.02   0.36 ± 0.02  0.38 ± 0.03

3 min

 0.34 ± 0.02  0.36 ± 0.02   0.36 ± 0.01 0.47 ± 0.01  
5 min  0.35 ± 0.01  0.35 ± 0.02  0.46 ± 0.01 0.44 ± 0.02  
10 min  0.36 ± 0.01  0.36 ± 0.02  0.44 ± 0.02   0.44 ± 0.01
15 min 0.36 ± 0.02  0.36 ± 0.02   0.42 ± 0.02  0.42 ± 0.02  
20 min  0.36 ± 0.02  0.36 ± 0.02   0.40 ± 0.02  0.38 ± 0.10  
40 min  0.38 ± 0.02  0.38 ± 0.02   0.38 ± 0.02  0.36 ± 0.03 
60 min  0.34 ± 0.02  0.34 ± 0.02   0.36 ± 0.01 0.36 ± 0.02
120 min  0.34 ± 0.01  0.34 ± 0.01   0.36 ± 0.02   0.36 ± 0.04
240 min  0.35 ± 0.01  0.35 ± 0.02   0.34 ± 0.02   0.36 ± 0.03 
360 min  0.34 ± 0.02  0.34 ± 0.02   0.36 ± 0.01  0.34 ± 0.02 

Adverse Events

 None listed

Study Author Conclusions

It may be concluded that Ondansetron in a dose of 1 mg in healthy adult participants can effectively prevent postoperative nausea and vomiting causing no or insignificant prolongation of QTc interval.

InpharmD Researcher Critique

The effects on QTc changes by different anesthetic agents could not be measured. Concurrent assessments of the QTc changes by the different anesthetic agents would have yielded better results for external validity.



References:

Gupta SD, Pal R, Sarkar A, et al. Evaluation of Ondansetron-induced QT interval prolongation in the prophylaxis of postoperative emesis. J Nat Sci Biol Med. 2011;2(1):119-124. doi:10.4103/0976-9668.82306